CN116850295A - Pharmaceutical composition, medicine and application for treating tumors - Google Patents
Pharmaceutical composition, medicine and application for treating tumors Download PDFInfo
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- CN116850295A CN116850295A CN202310923757.7A CN202310923757A CN116850295A CN 116850295 A CN116850295 A CN 116850295A CN 202310923757 A CN202310923757 A CN 202310923757A CN 116850295 A CN116850295 A CN 116850295A
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- tumor
- gastric cancer
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a pharmaceutical composition for treating tumors, a medicine and application thereof, and belongs to the technical field of combined medication. The invention provides a pharmaceutical composition for treating tumors, which is prepared by combining an anti-angiogenesis medicament and a HIF-1a inhibitor. The invention proves that the anti-angiogenesis treatment induced gastric cancer hypoxia microenvironment promotes the accumulation of intracellular HIF-1a, and the HIF-1a improves the hypoxia tolerance of cells by enhancing glucose metabolism reprogramming, so that gastric cancer cells keep activity in the hypoxia microenvironment. The invention can generate synergistic complementary effect by combining the anti-angiogenesis medicine apitinib and the HIF-1a inhibitor CAY 10585: exacerbating the hypoxia in the tumor of the gastric cancer, blocking the glucose metabolism reprogramming of gastric cancer cells, further enhancing the anti-tumor effect and inhibiting the progress of the gastric cancer.
Description
Technical Field
The invention belongs to the technical field of combined medication, and particularly relates to a pharmaceutical composition for treating tumors, a medicament and application.
Background
apitinib is a novel small molecule Tyrosine Kinase Inhibitor (TKI) which is independently researched and developed in China, and is targeted to bind with vascular endothelial growth factor receptor 2 (VEGFR-2), so that the angiogenesis in tumors can be effectively inhibited, the tumor progression can be inhibited, and the progression-free survival time and total survival time of patients with advanced tumors and metastatic tumors can be effectively prolonged. Patinib is the first antiangiogenic agent approved by the chinese food and drug administration for the treatment of metastatic gastric cancer. Currently, patinib has been proposed as a three-line therapy for patients with advanced gastric cancer and metastatic gastric cancer, effectively improving the survival prognosis of tumor patients by inhibiting tumor angiogenesis. However, anti-angiogenic therapy results in reduced blood supply within the tumor, exacerbating hypoxia within the tumor, while selective tumor cell subsets re-program by glucose metabolism to enhance hypoxia tolerance of the cells, resulting in failure of anti-angiogenic therapy.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition, a medicine and application for treating tumors, wherein the pharmaceutical composition or the medicine can overcome the problem of clinical anti-angiogenesis treatment resistance, weaken the hypoxia tolerance of tumor cells while resisting angiogenesis, and strengthen the anti-tumor effect.
The invention provides a pharmaceutical composition for treating tumors, which comprises an anti-angiogenesis drug and a HIF-1a inhibitor.
Preferably, the anti-angiogenic drug comprises at least one of: apatinib, bevacizumab and ramucirumab.
Preferably, the HIF-1a inhibitor comprises at least one of the following: CAY10585 and Lifiguruat (YC-1).
Preferably, the working concentration ratio of apitinib to CAY10585 is 120mg/kg:10mg/kg.
The invention also provides application of the pharmaceutical composition in preparing medicines for treating tumors.
Preferably, the treatment comprises at least one of:
(1) Inhibiting neovascularization within the tumor;
(2) Promoting the formation of anoxic microenvironment;
(3) Inhibiting tumor growth;
(4) Inhibit tumor metastasis.
The invention also provides a medicine for treating tumors, and the active ingredients comprise the pharmaceutical composition and pharmaceutically acceptable auxiliary materials.
Preferably, the mass percentage of the active ingredients is 0.1-99%.
Preferably, the dosage form of the medicament comprises an oral preparation, an intravenous injection or an intraperitoneal injection.
Preferably, the tumor comprises gastric cancer.
The beneficial effects are that: the invention provides a pharmaceutical composition for treating tumors, which is prepared by combining an anti-angiogenesis medicament and a HIF-1a inhibitor. The embodiment of the invention proves that the anti-angiogenesis treatment induced tumor hypoxia microenvironment promotes the accumulation of hypoxia inducible factor HIF-1a, the higher the hypoxia degree in the tumor is, the higher the expression of HIF-1a is, and the HIF-1a enhances the hypoxia tolerance of cells by enhancing glucose metabolism reprogramming, so that the tumor cells keep activity in the hypoxia microenvironment.
In the embodiment of the invention, the anti-angiogenesis medicine apitinib and the HIF-1a inhibitor CAY10585 can generate a synergistic and complementary effect through a combined treatment mode: apitinib inhibits tumor neovascularization, and the induced hypoxia microenvironment promotes HIF-a expression, so that the targeting of an HIF-a inhibitor CAY10585 is enhanced; CAY10585 blocks reprogramming of gastric cancer cell glucose metabolism and weakens hypoxia tolerance of tumor cells. The combined treatment of apitinib and CAY10585 is helpful for overcoming the problem of clinical anti-angiogenesis treatment resistance, weakening the hypoxia tolerance of tumor cells while resisting angiogenesis, and enhancing the anti-tumor effect. The invention also proves by in vivo experiments of mice: apitinib is effective in inhibiting tumor neovascularization, reducing tumor blood supply, and promoting anoxic microenvironment. The combined treatment of apitinib and CAY10585 effectively inhibits the growth and metastasis of tumors, enhances the anti-tumor effect and inhibits the development of the tumors.
Drawings
FIG. 1 is a flow chart of an in vivo therapeutic assay of the present invention;
FIG. 2 is a graph of the results of the correlation of anti-angiogenic therapy induced hypoxia microenvironment with HIF-1 a;
FIG. 3 is a graph showing the correlation between HIF-1a and cellular glucose metabolism reprogramming and cellular hypoxia tolerance;
FIG. 4 is a graph showing the results associated with inhibition of reprogramming of gastric cancer cell glucose metabolism and hypoxia tolerance by the HIF-1a inhibitor CAY 10585;
FIG. 5 is a graph showing the effect of the combination therapy of apitinib and CAY10585 on anti-tumor effects.
Detailed Description
The invention provides a pharmaceutical composition for treating tumors, which comprises an anti-angiogenesis drug and a HIF-1a inhibitor.
The anti-angiogenic drug of the present invention preferably comprises that the anti-angiogenic drug comprises at least one of the following: apatinib, bevacizumab and ramucirumab; the HIF-1a inhibitors include at least one of the following: CAY10585 and Lifiguruat (YC-1); in the examples, the combination of apitinib and CAY10585 is exemplified, and the administration of the anti-vascular agent apitinib (oral gavage, 120mg/kg, daily) is started on day 10, and CAY10585 (oral gavage, 10mg/kg, daily) is started on day 24, where the establishment of the model of gastric carcinoma in situ was successful. The source of the apiinib and CAY10585 is not particularly limited, and the commercially available products which are common in the art can be used.
The invention also provides application of the pharmaceutical composition in preparing medicines for treating tumors.
The CAY10585 is an effective hypoxia inducible factor HIF-1a inhibitor, and can inhibit the accumulation of intracellular HIF-1a in a hypoxia state. HIF-1a is responsible for activating transcription of genes involved in hypoxia homeostasis as a key transcription factor for cell sensing external oxygen changes. The research finds that the HIF-1a is highly enriched in the gastric cancer hypoxia microenvironment, and the HIF-1a can improve the hypoxia tolerance of gastric cancer cells by regulating and controlling glucose metabolism reprogramming of gastric cancer cells, so that the gastric cancer cells keep activity in the hypoxia microenvironment and evade apoptosis or death. Thereby resulting in resistance to anti-angiogenic therapy of gastric cancer. Based on the molecular mechanism, the combined treatment of apitinib and CAY10585 is used for inhibiting tumor angiogenesis and simultaneously blocking glucose metabolism reprogramming of tumor cells, overcoming the resistance of anti-angiogenesis treatment and inhibiting tumor progression.
The treatment according to the invention preferably comprises at least one of the following:
(1) Inhibiting neovascularization within the tumor;
(2) Promoting the formation of anoxic microenvironment;
(3) Inhibiting tumor growth;
(4) Inhibit tumor metastasis.
The invention also provides a medicine for treating tumors, and the active ingredients comprise the pharmaceutical composition and pharmaceutically acceptable auxiliary materials.
The mass percentage of the active ingredients is preferably 0.1-99%. The dosage form of the medicament of the present invention preferably includes an oral preparation, an intravenous injection or an intraperitoneal injection.
For further explanation of the present invention, a pharmaceutical composition for treating tumor, a medicament and application provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
1. Experimental method
1. In vitro treatment experiments:
the material sources are as follows: HIF-1a inhibitor CAY10585 was purchased from Selleck corporation (product number S8441) experimental procedure:
(1) Cell culture: the cells were conditioned to a good state, digested with 0.25% EDTA pancreatin when the cells were in the logarithmic growth phase, inoculated into 24 well plates, and placed at 37℃with 5% CO 2 Is continuously cultured in a cell incubator; after the cell adheres to the wall, changing the cobalt chloride-containing CoCl 2 (100 μm) complete medium, mimicking an in vitro hypoxic environment;
(2) Drug treatment: the addition of the HIF-1a inhibitor CAY10585 (0.7. Mu.M) to Kong Zhongshang clear stimulates gastric cancer cells
(3) Colorimetric detection of gastric cancer cell glucose uptake rate and lactate production rate changes, reflecting the reprogramming changes of cell glucose metabolism
2. In vivo treatment experiments (gastric cancer in situ tumor model treatment experiments):
the material sources are as follows: HIF-1a inhibitor CAY10585 was purchased from Selleck corporation (product number S8441), and apiinib was purchased from Selleck corporation (product number S5248)
The experimental steps are as follows:
(1) Building a gastric cancer in-situ planting tumor model:
(a) Preparing 4-6 week old athymic nude mice, male, weighing 18-20g, and breeding in SPF environment;
(b) Nude mice subcutaneous tumor model construction: the gastric cancer cells with good state were prepared as single cell suspension (5×10) 7 And/ml). After disinfection with 75% alcohol, cell suspension was injected (subcutaneous injection, 200 μl/mouse) into the groin on the right side of nude mice, and tumor growth was observed periodically after inoculation with gastric cancer cells;
(c) When the subcutaneous tumor grows to 1.0-1.5cm, the nude mice are euthanized by dislocation, tumor mass is peeled off and cut into several parts (about 1mm in size) with a sterile knife blade 3 ) Placing in Hanks buffer solution for standby;
(d) Planting in situ: after inhalation anesthesia with diethyl ether and alcohol sterilization of the skin of the surgical area, the nude mice were incised along the left median bystander line and carefully exposed the peritoneum and stomach wall; suturing the tumor mass to the stomach wall using absorbable suture, and suturing the abdomen;
(2) Grouping design and drug treatment:
randomly dividing the successfully constructed nude mice into a Control group (Control), an apiinib treatment group and an apiinib+CAY 10585 treatment group, wherein 6 nude mice/group; in situ, on day 10 after implantation, nude mice were treated with apetinib (120 mg/kg. Day, lavage; apetinib treatment group, apetinib+cay10585 treatment group), control nude mice were treated with an equal volume of DMSO solution; treatment with CAY10585 (10 mg/kg. Day, lavage; apatinib+CAY10585 treatment group) was performed on day 24 post-surgery, and Control (Control) and apatinib treatment groups were performed with equal volumes of DMSO solution;
(3) Observing the growth and transfer conditions of in-situ planting tumor: killing nude mice after 8 weeks of operation, fully probing the pleuroperitoneal cavity, taking out the abdominal cavity for in-situ tumor implantation, measuring the size of tumor blocks, and carrying out hematoxylin-eosin staining and immunohistochemical detection after formalin fixation; at the same time, tumor metastasis conditions (adjacent organ metastasis conditions, etc.) of the thoracic and abdominal cavities of the nude mice were observed.
2. Experimental results
1. The hypoxia microenvironment induced by anti-angiogenic therapy promotes HIF-accumulation (fig. 2).
By cobalt chloride (CoCl) 2 ) In vitro hypoxia model analysis showed that the degree of hypoxia (CoCl) 2 Concentration) and the higher the level of intracellular HIF-1a expression (FIG. 2A). The gastric cancer tissue of human body is detected by immunofluorescence, and the gastric cancer tissue hypoxia-inducible factor HIF-1a in the hypoxia area is obviously enriched (B in figure 2). Further using apiinib to construct an anti-angiogenic therapeutic resistance model, hypoxia microenvironment within the subcutaneous tumor of mice was induced (C in fig. 2), immunofluorescence results showed that the neovasculature within the subcutaneous tumor of the apiinib-treated mice was significantly reduced and the HIF-1a expression was significantly increased (D in fig. 2).
2. Hypoxia inducible factor HIF-1a increases hypoxia tolerance of cells by enhancing reprogramming of glucose metabolism of cells (FIG. 3)
Glucose metabolism reprogramming is an important intrinsic mechanism of tumor progression, a characteristic metabolic change of tumors. Glucose metabolism in normal cells is in an equilibrium state, and Adenosine Triphosphate (ATP) is synthesized mainly through mitochondrial oxidative phosphorylation processes to supply energy; however, the tumor cells are in a glucose hypermetabolic state, and the cell energy supply mode is regulated through the Warburg effect, so that the glucose metabolism mode is changed from dependent on mitochondrial oxidative phosphorylation to dependent on glycolysis, namely, the reprogramming of glucose metabolism is realized.
By CoCl 2 In vitro hypoxia model, intracellular level of HIF-1a is significantly up-regulated after hypoxia (fig. 3 a), glucose uptake rate and lactate production level of gastric cancer cells are significantly up-regulated; furthermore, the higher the degree of hypoxia, the higher the glycolysis level of gastric cancer cells (B in fig. 3). At the same time, the mitochondrial membrane potential of gastric cancer cells was significantly decreased and mitochondrial function was inhibited in the hypoxic state (C in fig. 3). Enhancement of proliferation and migration ability of gastric cancer cells in the hypoxic state was seen by inhibiting mitochondrial function of gastric cancer cells and enhancing cell glycolysis using ATPase inhibitor oligomycin na (D and E in fig. 3). The experimental result shows that the expression of HIF-1a in the anoxic state is up-regulated to promote the glucose metabolism reprogramming of gastric cancer cells, the gastric cancer cell productivity mode is changed from the oxidative phosphorylation of mitochondria to dependent glycolysis, so that the gastric cancer cells have better activity in the anoxic microenvironment, and the anoxic tolerance of the gastric cancer cells is improved.
CAY10585 is effective in inhibiting glucose metabolism reprogramming and impairing hypoxia tolerance of gastric cancer cells (FIG. 4)
In this study, gastric cancer cells were stimulated with CAY10585 (0.7M), and it was found that the glucose uptake rate and lactic acid production rate of gastric cancer cells were significantly reduced after stimulation with CAY10585 in the anoxic state, suggesting that glycolysis levels were inhibited (fig. 4 a). The changes in gastric cancer cell proliferation and migration ability were further detected by CCK8 and scratch experiments, respectively (B and C in fig. 4). Experimental results show that after being stimulated by CAY10585 (anoxic state), the proliferation capacity and migration capacity of gastric cancer cells are obviously weakened, which suggests that the reprogramming of gastric cancer cells by glucose after being stimulated by CAY10585 is blocked, the hypoxia tolerance of the cells is reduced, and the activity of gastric cancer cells in an anoxic environment is damaged.
Combination therapy of apitinib with CAY10585 potentiates the anti-tumor effect and overcomes the anti-angiogenic therapeutic resistance (FIG. 5)
In-vitro cell therapy experiments show that CAY10585 effectively inhibits glycolysis of gastric cancer cells and inhibits proliferation and migration capacity of gastric cancer cells in an anoxic state. Further constructing a mouse gastric cancer in-situ tumor implantation model (A in figure 1) for in-vivo drug treatment experiments. The Control group (Control), the apitinib group, and the combination treatment group of apitinib and CAY10585 were established, respectively, and the therapeutic effect of the anti-angiogenic drug in combination with the HIF-1a inhibitor was examined (B in FIG. 1). Experimental results show that the anti-angiogenesis drug apitinib can effectively inhibit the progress of gastric cancer, and the combined treatment group of apitinib and CAY10585 shows stronger anti-tumor effect, so that the abdominal metastasis of gastric cancer is obviously reduced, and the tumor growth is inhibited (A in figure 5); the tumor mass properties of gastric carcinoma in situ-grown tumors and intestinal metastases were further confirmed by hematoxylin-eosin staining (HE) staining (fig. 5B). In conclusion, animal experiments prove that the combined treatment of the apitinib and the CAY10585 can effectively inhibit the growth and metastasis of gastric carcinoma in-situ plantation tumor, and enhance the anti-tumor effect.
Although the foregoing embodiments have been described in some, but not all, embodiments of the invention, it should be understood that other embodiments may be devised in accordance with the present embodiments without departing from the spirit and scope of the invention.
Claims (10)
1. A pharmaceutical composition for treating a tumor, comprising an anti-angiogenic agent and a HIF-1a inhibitor.
2. The pharmaceutical composition of claim 1, wherein the anti-angiogenic drug comprises at least one of: apatinib, bevacizumab and ramucirumab.
3. The pharmaceutical composition of claim 1 or 2, wherein the HIF-1a inhibitor comprises at least one of the following: CAY10585 and Lifiguruat (YC-1).
4.A pharmaceutical composition according to claim 3, wherein the working concentration ratio of apitinib and CAY10585 is 120mg/kg:10mg/kg.
5. Use of a pharmaceutical composition according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of a tumor.
6. The use according to claim 5, wherein the treatment comprises at least one of:
(1) Inhibiting neovascularization within the tumor;
(2) Promoting the formation of anoxic microenvironment;
(3) Inhibiting tumor growth;
(4) Inhibit tumor metastasis.
7. A medicament for treating tumors, which is characterized in that the active ingredient comprises the pharmaceutical composition according to any one of claims 1 to 4 and further comprises pharmaceutically acceptable auxiliary materials.
8. The medicine according to claim 7, wherein the mass percentage of the active ingredient is 0.1-99%.
9. The medicament of claim 7, wherein the dosage form of the medicament comprises an oral, intravenous or intraperitoneal injection.
10. The medicament of claim 7, wherein the tumor comprises gastric cancer.
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